WO2008055959A1 - Nouveaux composés utilisés dans le traitement de maladies dégénératives et inflammatoires - Google Patents

Nouveaux composés utilisés dans le traitement de maladies dégénératives et inflammatoires Download PDF

Info

Publication number
WO2008055959A1
WO2008055959A1 PCT/EP2007/062085 EP2007062085W WO2008055959A1 WO 2008055959 A1 WO2008055959 A1 WO 2008055959A1 EP 2007062085 W EP2007062085 W EP 2007062085W WO 2008055959 A1 WO2008055959 A1 WO 2008055959A1
Authority
WO
WIPO (PCT)
Prior art keywords
cpc
pyrazolo
pyrimidin
substituted
alkyl
Prior art date
Application number
PCT/EP2007/062085
Other languages
English (en)
Inventor
Paul Edwards
Mark Stuart Chambers
Christel Jeanne Marie Menet
Stephen Robert Fletcher
Rebecca Elizabeth Jarvis
Hervé VAN DE POËL
Alexander Sudau
Alastair Rae
Peter Stanley Thomas
Original Assignee
Galapagos N.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Galapagos N.V. filed Critical Galapagos N.V.
Publication of WO2008055959A1 publication Critical patent/WO2008055959A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to compounds that are inhibitors of PDElA, a phosphodiesterase that is involved in the modulation of the degradation of cartilage, joint degeneration and diseases involving such degradation and/or inflammation.
  • Cartilage is an avascular tissue of which chondrocytes are the main cellular component.
  • the chondrocytes in normal articular cartilage occupy approximately 5% of the tissue volume, while the extra-cellular matrix makes up the remaining 95% of the tissue.
  • the chondrocytes secrete the components of the matrix, mainly proteoglycans and collagens, which in turn supply the chondrocytes with an environment suitable for their survival under mechanical stress.
  • collagen type II together with the protein collagen type IX, is arranged in solid fibril-like structures, which provide cartilage with great mechanical strength.
  • the proteoglycans can absorb water and are responsible for the resilient and shock absorbing properties of the cartilage.
  • cartilage degradation is caused by the secretion of proteases (e.g. collagenases) by inflamed tissues (the inflamed synovium for example).
  • cartilage degradation can also be the result of an injury of the cartilage, due to an accident or surgery, or exaggerated loading or 'wear and tear'.
  • the ability of cartilage tissue to regenerate after such insults is limited. Chondrocytes in injured cartilage often display reduced cartilage synthesizing (anabolic) activity and/or increased cartilage degrading (catabolic) activity.
  • Rheumatoid arthritis is a chronic joint degenerative disease, characterized by inflammation and destruction of the joint structures. When the disease is unchecked, it leads to substantial disability and pain due to loss of joint functionality and even premature death. The aim of an RA therapy, therefore, is not to slow down the disease but to attain remission in order to stop the joint destruction. Besides the severity of the disease outcome, the high prevalence of RA ( ⁇ 0.8% of adults are affected worldwide) means a high socio-economic impact. (For reviews on RA, we refer to Smolen and Steiner (2003); Lee and Weinblatt (2001); Choy and Panayi (2001); O'Dell (2004) and Firestein (2003)).
  • Osteoarthritis also referred to as OA, or wear-and-tear arthritis
  • OA wear-and-tear arthritis
  • the disease mainly affects hands and weight-bearing joints such as knees, hips and spines. This process thins the cartilage.
  • grade I osteoarthritis When the surface area has disappeared due to the thinning, a grade I osteoarthritis is reached; when the tangential surface area has disappeared, grade II osteoarthritis is reached.
  • grade II osteoarthritis There are further levels of degeneration and destruction, which affect the deep and the calcified cartilage layers that border with the subchondral bone.
  • the clinical manifestations of the development of the osteoarthritis condition include: increased volume of the joint, pain, crepitation and functional disability that, lead to pain and reduced mobility of the joints. When disease further develops, pain at rest emerges. If the condition persists without correction and/or therapy, the joint is destroyed leading to disability. Replacement surgery with total prosthesis is then required.
  • Osteoarthritis is difficult to treat. At present, no cure is available and treatment focuses on relieving pain and preventing the affected joint from becoming deformed. Common treatments include the use of non-steroidal anti- inflammatory drugs (NSAID's). Although the dietary supplements as chondroitin and glucosamine sulphate have been advocated as safe and effective options for the treatment of osteoarthritis, a recent clinical trial revealed that both treatments did not reduce pain associated to osteoarthritis. (Clegg et al., 2006). Taken together, no disease modifying osteoarthritic drugs are available.
  • NSAID's non-steroidal anti- inflammatory drugs
  • chondral cellular material is taken from the patient, sent to a laboratory where it is expanded. The material is then implanted in the damaged tissues to cover the tissue's defects.
  • Another treatment includes the intra-articular instillation of Hylan G-F 20 (Synvisc,
  • Hyalgan, Artz etc. a substance that improves temporarily the rheology of the synovial fluid, producing an almost immediate sensation of free movement and a marked reduction of pain.
  • Other reported methods include application of tendinous, periosteal, fascial, muscular or perichondral grafts; implantation of fibrin or cultured chondrocytes; implantation of synthetic matrices, such as collagen, carbon fiber; administration of electromagnetic fields. All of these have reported minimal and incomplete effects, resulting in a poor quality tissue that can neither support the weighted load nor allow the restoration of an articular function with normal movement.
  • Stimulation of the anabolic processes, blocking catabolic processes, or a combination of these two, may result in stabilization of the cartilage, and perhaps even reversion of the damage, and therefore prevent further progression of the disease.
  • Various triggers may stimulate anabolic stimulation of chondrocytes.
  • Insulin-like growth factor-I IGF-I is the predominant anabolic growth factor in synovial fluid and stimulates the synthesis of both proteoglycans and collagen.
  • BMP bone morphogenetic protein
  • TGF-b human transforming growth factor-b
  • Adenosine 3', 5'-cyclic monophosphate (cyclic AMP or cAMP) and guanosine 3', 5'- cyclic monophosphate (cyclic GMP or cGMP) are key second messenger molecules in cells which are synthesized by guanylyl and adenylyl cyclases. These molecules, by playing a role as 'relay' on signal transduction pathways, are key in controlling normal and pathological cell responses. Cyclic nucleotide phosphodiesterases (PDE's) are enzymes that hydrolyse cyclic nucleotides and thereby control the cellular levels of these second messenger molecules. Because of their key role in cellular signaling, PDE's are considered new therapeutic targets.
  • PDE's are enzymes that hydrolyse cyclic nucleotides and thereby control the cellular levels of these second messenger molecules. Because of their key role in cellular signaling, PDE's are considered new therapeutic targets.
  • PDE4 and PDE5 are accepted approaches for the treatment of asthma/chronic obstructive pulmonary disease and erectile dysfunction, respectively.
  • pharmaceutical industry has recently deployed a lot of efforts to develop PDE4 inhibitors (e.g. Cilomilast) and PDE5 inhibitors (e.g. sildenafil), some of which are marketed.
  • the ILl cytokine is responsible for cartilage catabolism by reducing the expression of matrix components, by inducing the expression of collagenases and inducible nitric oxide synthase (iNOS), which mediates the production of nitric oxide (NO).
  • iNOS inducible nitric oxide synthase
  • This event appears dependent on PDE activity, as IBMX, PDE5 inhibitor and PDE4 inhibitor treatment of chondrocytes reduced the induction of iNOS expression by ILl (Geng et al., 1998, Tenor et al., 2002).
  • the ability of PDE inhibitors to reduce iNOS expression appeared dependent on autocrine PGE2 production by the chondrocytes. Taken together, these data suggest a role for PDEs in cartilage catabolic events.
  • the current therapies are not satisfactory and therefore there remains a need to identify further compounds that may be of use in the treatment of degenerative joint diseases, e.g. osteoarthritis, rheumatoid arthritis and osteoporosis, in particular osteoarthritis.
  • the present invention therefore provides compounds, methods for their manufacture and a pharmaceutical comprising a compound of the invention together with a suitable pharmaceutical carrier.
  • the present invention also provides for the use of a compound of the invention in the preparation of a medicament for the treatment of degenerative joint diseases.
  • the present invention is based on the discovery that inhibitors of PDElA are useful for the treatment of diseases involving cartilage degradation, joint degradation and/or inflammation, for example osteoarthritis.
  • the present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for treating diseases involving cartilage degradation, joint degradation and/or inflammation by administering a compound of the invention.
  • the compounds of the present invention may be described generally as pyrazolo[3,4- d]pyrimidin-4-ones substituted in the 6-position with a C-linked nitrogen substituted cycloalkylamine.
  • the present invention relates to compounds having anti- inflammatory properties, according to formula (I):
  • B represents bond, CpC 6 alkyl, (CH 2 ) m -cycloalkyl, -(CH 2 ) m -heterocycloalkyl, (CH 2 ) m -aryl or (CH 2 ) m .heteroaryl optionally substituted with one or more groups selected from halogen, CN, CF 3 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 4 R 5 , CpC 6 alkyl, (CH 2 ) n - heterocycloalkyl (optionally substituted by CpC 6 alkyl), NO 2 , OR 4 , COR 4 , CO 2 R 4 , or SO 2 R 4 X represents a carbon-carbon bonded nitrogen-containing heterocycloalkyl group; R 1 represents H, CpC 6 alkyl, (CH 2 ) n -aryl, cycloalkyl or - Cp
  • R 2 represents H, CpC 6 alkyl, cycloalkyl, heterocycloalkyl, (CH 2 ) n -aryl, or a (CH 2 ) n -heteroaryl group, each of which may optionally be substituted with one or more groups selected from halogen, CN, CF 3 , NR 4 R 5 , NHCOR 4 , CONH 2 , NHSO 2 R 4 , SO 2 NHR 4 , SO 2 R 4 , CpC 6 alkyl, OR 4 , COR 4 , CO 2 R 4 , or SO 2 R 4 ;
  • R 3 represents H, halogen, CpC 6 alkyl, cycloalkyl, (CH 2 ) n -aryl, aryl, or a heteroaryl group, each of which may optionally be substituted with one or more groups selected from halogen, CN, CF 3 , NR 4 R 5 , NHCOR 4 , CONH 2 , NHSO 2 R 4 , SO 2 NHR 4 , SO 2 R 4 , CpC 6 alkyl, CpC 6 alkoxy, COR 4 , CO 2 R 4 , or SO 2 R 4 ; each R 4 independently represents H, CpC 6 alkyl, cycloalkyl, heterocycloalkyl, CF 3 or CHF 2 ; R 5 represents H, CpC 6 alkyl, or cycloalkyl; and each "n" independently represents O, 1, 2 or 3; "m” represents O, 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof
  • the present invention relates to compounds having antiinflammatory properties, according to formulae Ia, Ib, Ic, Id, Ie, If, Ig or Ih:
  • X represents a carbon-carbon bonded nitrogen-containing heterocycloalkyl group
  • B represents substituted or unsubstituted CpC 6 alkyl, or CpC 6 haloalkyl; or B represents substituted or unsubstituted cycloalkyl, heterocycloalkyl, or cycloalkylalkyl; or B represents substituted or unsubstituted aralkyl, aryl or heteroaryl; or with respect to a compound according to the formulae Ie or Ig, B further includes H, NO 2 , Ci-C 6 alkyl, halo, -CO-aryl, -CO-heteroaryl, -CON(R 4 )-aryl, or CO-N(R 4 )- heteroaryl;
  • Y represents a bond, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; the group B-(CH 2 )n-, B-CO-, B-N(R 10 )CO-, B-SO 2 -, B-OCO-, B-N(R 10 )SO 2 -, B-Y- or B- NR 10 -D(R 9 )- is linked to X via a nitrogen atom within the X group;
  • D represents CH or N, with the proviso that when D represents CH, R 9 represents -NO 2 and when D represents N, R 9 represents CN;
  • R 1 represents H, CpC 6 alkyl, (CH 2 )n-aryl, cycloalkyl or - CpC 6 alkyl-cycloalkyl group, each of which may optionally be substituted with one or more groups selected from halogen, CN, CF 3 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , C r C 6 alkyl, C r C 6 alkoxy, COR 4 , CO 2 R 4 , or SO 2 R 4 ;
  • R 2 represents H, CpC 6 alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, (CH 2 )n-aryl, or a heteroaryl group, each of which may optionally be substituted with one or more groups selected from halogen, CN, NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , CpC 6 alkyl, CpC 6 haloalkyl, CpC 6 alkoxy, C1-C6 haloalkoxy, COR 4 , CO 2 R 4 , or SO 2 R 4 ;
  • R 3 represents H, halogen, CpC 6 alkyl, cycloalkyl, (CH 2 )n-aryl, aryl, or a heteroaryl group, each of which may optionally be substituted with one or more groups selected from halogen, CN, NR 4 R 5 , N R 5 COR 4 , CON R 4 R 5 , NR 5 SO 2 R 4 , SO 2 N R 5 R 4 , CpC 6 alkyl, CpC 6 haloalkyl, Cp C 6 alkoxy, CpC 6 haloalkoxy, COR 4 , CO 2 R 4 , or SO 2 R 4 ;
  • R 4 represents H, CpC 6 alkyl, halo CpC 6 alkyl, cycloalkyl, or heterocycloalkyl;
  • R 5 represents H, CpC 6 alkyl, or cycloalkyl
  • R 9 represents CN or NO 2 ;
  • R 10 represents H or CpC 6 alkyl; and each "n" independently represents O, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof or isotopic variants thereof, stereoisomers or tautomers thereof.
  • X is selected from piperidine, pyrrolidine and azetidine.
  • X is piperidine or azetidine.
  • Another aspect of this invention relates to the use of the present compound in a therapeutic method, a pharmaceutical composition, and the manufacture of such composition, useful for the treatment of a disease involving inflammation, and in particular, a disease characteristic of abnormal PDElA activity. This invention also relates to processes for the preparation of the present compounds.
  • Figure 1 Shows the mechanism of the primary screening assay using the cAMP dynamic htrf kit from Cisbio.
  • halo such as fluoro, chloro, bromo
  • -CN -CF 3 , - OH, -OCF 3
  • Ci-C 6 alkyl C 2 -C 6 alkenyl, C 3 -C 6 alkynyl, CpC 6 alkoxy, aryl and di- CpC 6 alkylamino.
  • groups and “radicals” can be considered interchangeable when used herein.
  • analogue means one analogue or more than one analogue.
  • alkoxy means alkyl-O-.
  • Exemplary alkoxy includes methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, and heptoxy.
  • Preferred alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms.
  • alkyl means straight or branched aliphatic hydrocarbon having 1 to about 20 carbon atoms.
  • alkyl has 1 to about 12 carbon atoms.
  • a further particular group is lower alkyl which has 1 to 6 carbon atoms.
  • Further particular groups are groups such as methyl, ethyl and propyl. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain.
  • the term CpC 6 alkyl includes both branched and straight chain groups, exemplary straight chain groups include ethyl, propyl, butyl as listed above, exemplary branched chain groups include isopropyl, isoamyl.
  • alkyl amino means alkyl-NH-.
  • Preferred alkyl amino is (Ci-C 6 )-alkyl amino.
  • Exemplary alkyl amino includes methylamino and ethylamino.
  • 'Amino lower alkanoyl means NH 2 -R-CO-, where R is lower alkylene.
  • Preferred groups include aminoethanoyl and aminoacetyl.
  • 'Aralkyl' or 'arylalkyl' refers to a radical in which an aryl group is substituted for a hydrogen atom of an alkyl group.
  • 'Acyl' refers to a radical -C(O)R 20 , where R 20 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined herein.
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.
  • Aryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Aryl groups may be monocyclic or a bicyclic fused-ring structure where at least one of the rings is an aromatic ring structure that preferentially contains 6 carbons.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta 2,4 diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like.
  • an aryl group comprises from 6 to
  • Aryl' includes those groups recited in the definition of "substituted” herein, and particularly refers to an aryl group that may optionally be substituted with 1 or more substituents, for instance from 1 to 5 substituents, particularly 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkoxycarbonyl, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thiol, alkyl
  • 'Bicycloaryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent bicycloaromatic ring system.
  • Typical bicycloaryl groups include, but are not limited to, groups derived from indane, indene, naphthalene, tetrahydronaphthalene, and the like. Particularly, an aryl group comprises from 8 to 11 carbon atoms.
  • Carbamoyl' refers to the radical -C(O)N(R 42 ) 2 where each R 42 group is independently hydrogen, alkyl, cycloalkyl or aryl, as defined herein, which may be optionally substituted as defined herein.
  • the term "carbamoyl” refers to -C(O)-NH 2 .
  • 'carbamoyl lower alkyl' means the radical NH 2 CO-lower alkyl-.
  • Preferred carbamoyl lower alkyl groups include carbamoylethyl and carbamoylmethyl.
  • Carboxy lower alkyl ester' means a lower alkyl ester of a carboxy radical, -COO- group.
  • 'Halo' or 'halogen' means fluoro, chloro, bromo, or iodo.
  • 'Hydrogen means in the context of a substituent that -H is present at the compound position and also includes its isotope, deuterium.
  • 'Lower alkyl' means 1 to about 6 carbon atoms in a linear alkyl chain that may be straight or branched.
  • 'Lower alkoxy' means 1 to about 6 carbon atoms in a linear alkyl chain that may be straight or branched, and that is bonded by an oxygen atom.
  • 'Lower alkyl sulphonamide' refers to a lower alkyl amide of sulphonamide of the formula -SO2NR*R*, where R* is hydrogen or lower alkyl, and at least one R* is lower alkyl.
  • 'Sulphonamide' refers to a group of compounds containing the chemical group -
  • 'Cycloalkyl' refers to cyclic hydrocarbyl groups having from 3 to about 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems, which optionally can be substituted with from 1 to 3 alkyl groups.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1 -methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, and multiple ring structures such as adamantanyl, and the like.
  • cycloalkyl groups have between 4 and 7 carbon ring members for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • 'Substituted cycloalkyl' includes those groups recited in the definition of 'substituted' herein, and particularly refers to a cycloalkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto
  • 'Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • R 5 and R 5 may be hydrogen and at least one of R 5 and R 5 is each independently selected from alkyl, alkenyl, alkynyl, cycloheteroalkyl, alkanoyl, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 54 COR 55 , NR 54 SOR 55 , NR 54 SO2R 57 , COO- alkyl, COO-aryl, CONR 54 R 55 , CONR 54 OR 55 , NR 54 R 55 , SO2NR 54 R 55 , S-alkyl, S-alkyl, SO-alkyl, SO 2 - alkyl, S-aryl, SO-aryl, SO 2 -aryl; or R 52 and R 53 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O
  • R 54 , R 55 , and R 56 are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, cycloalkyl, cycloheteroalkyl, aryl, substituted aryl, heteroaryl, substituted or hetero alkyl or the like.
  • 'Hetero' when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g.
  • heterocycloalkyl aryl, e.g. heteroaryl, cycloalkenyl, heterocycloalkenyl, and the like having from 1 to 5, and especially from 1 to 3 heteroatoms.
  • Heteroaryl' refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
  • the heteroaryl group may be a monocyclic group (in which case it will typically be a 5 to 7, more typically a 5 or 6 membered ring), alternatively the heteroaryl group may be a bicycloheteroaryl group in particular a fused ring system comprising 2 fused 5-membered rings, a fused 5 and 6 membered ring or two fused 6 membered rings, where the heteroaryl group comprises fused rings at least one of said rings should contain a heteroatom and at least one said rings should be aromatic (both requirements may or may not be fulfilled in the same ring).
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring which may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen.
  • heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, ⁇ - carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine
  • the heteroaryl group is between 5-15 membered heteroaryl, with 5-10 membered heteroaryl being particularly preferred.
  • Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
  • examples of five membered heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups.
  • examples of six membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
  • Examples of representative heteroaryls include the following:
  • each Y is selected from carbonyl, N, NR 58 , O, and S; and R 58 is independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl or the like.
  • 'Bicycloheteroaryl' refers to a monovalent bicycloheteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent bicycloheteroaromatic ring system.
  • Typical bicycloheteroaryl groups include, but are not limited to, groups derived from benzofuran, benzimidazole, benzindazole, benzdioxane, chromene, chromane, cinnoline, phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, pteridine, purine, benzopyran, benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolizine, quinoxaline, benzomorphan, tetrahydroisoquinoline, tetrahydroquinoline, and the like.
  • the bicycloheteroaryl group is between 9-11 membered bicycloheteroaryl, with 5-10 membered heteroaryl being particularly preferred.
  • Particular bicycloheteroaryl groups are those derived from benzothiophene, benzofuran, benzothiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole, benzo[l,3]dioxalyl and benzodioxane.
  • Heterocycloalkyl refers to a stable heterocyclic non-aromatic ring and fused rings containing one or more heteroatoms independently selected from N, O and S.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • heterocyclic rings include, but are not limited to, piperazinyl, homopiperazinyl, piperidinyl and morpholinyl, and are shown in the following illustrative examples:
  • each X is selected from CR 58 2 , NR 58 , O and S; and each Y is selected from NR 58 , O and S; and R 58 is independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl or the like.
  • cycloheteroalkyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -.
  • Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivative
  • Nitrogen-Containing Heterocycloalkyl means a 4 to 7 membered non- aromatic cyclic group containing at least one Nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2- pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.
  • Examples of representative aryl having hetero atoms containing substitution include the following:
  • each X is selected from CR 58 2 , NR 58 , O and S; and each Y is selected from carbonyl, NR 58 , O aanndd SS;; aanndd RR 5588 iiss iinndependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl or the like.
  • aanndd RR 5588 iiss iinndependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl or the like.
  • 'Sulfonyl' refers to the group -SO 2 R 63 .
  • R 63 is selected from H, lower alkyl, alkyl, aryl and heteroaryl.
  • 'Pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • 'Pharmaceutically acceptable vehicle refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • 'Pharmaceutically acceptable salt refers to the non-toxic, inorganic and organic acid addition salts, and base addition salts, of compounds of the present invention, in particular they are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. These salts can be prepared in situ during the final isolation and purification of compounds useful in the present invention.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to a non toxic, acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • Solvate' means a physical association of a compound useful in this invention with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolable solvates.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. Conventional solvents include water, ethanol, acetic acid and the like, therefore, representative solvates include hydrates, ethanolates and methanolates.
  • 'Prodrugs' refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • 'Isotopic variant' refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound.
  • an "isotopic variant" of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium ( H or D), carbon 13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • the following atoms, where present, may vary, so that for example, any hydrogen may be 2H/D, any carbon may be 13 C, or any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • compounds may be prepared that are substituted with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention.
  • isomers compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers”. Isomers that differ in the arrangement of their atoms in space are termed
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H).
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • 'Subject' includes humans.
  • the terms 'human', 'patient' and 'subject' are used interchangeably herein.
  • 'Prophylaxis' means a measure taken for the prevention of a disease.
  • 'Preventing' or 'prevention' refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.
  • 'Therapeutically effective amount means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a subject that is being sought by a medical doctor or other clinician.
  • the "therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • the compounds of the present invention may be described generally as pyrazolo[3,4- d]pyrimidin-4-ones substituted in the 6-position with a C-linked nitrogen substituted cycloalkylamine. [0080] Accordingly, the present invention relates to compounds having anti-inflammatory properties, according to formula (I):
  • B represents H, Ci-C 6 alkyl, (CH 2 ) m -cycloalkyl, -(CH 2 ) m -heterocycloalkyl, (CH 2 ) m -aryl or
  • X represents a carbon-carbon bonded nitrogen-containing heterocycloalkyl group
  • R 1 represents H, CpC 6 alkyl, (CH 2 ) n -aryl, cycloalkyl Or -CpC 6 alkyl-cycloalkyl group, each of which may optionally be substituted with one or more groups selected from halogen, CN, CF 3 ,
  • R 2 represents H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, (CH 2 ) n -aryl, or a (CH 2 ) n -heteroaryl group, each of which may optionally be substituted with one or more groups selected from halogen, CN, CF 3 , NR 4 R 5 , NHCOR 4 , CONH 2 , NHSO 2 R 4 , SO 2 NHR 4 , SO 2 R 4 , CpC 6 alkyl, OR 4 ,
  • R represents H, halogen, Ci-Ce alkyl, cycloalkyl, (CH 2 ) n -aryl, aryl, or a heteroaryl group, each of which may optionally be substituted with one or more groups selected from halogen,
  • each R 4 independently represents H, CpC 6 alkyl, cycloalkyl, heterocycloalkyl, CF 3 or CHF 2 ;
  • R 5 represents H, Ci-C ⁇ alkyl, or cycloalkyl; and each "n" independently represents O, 1, 2 or 3;
  • m represents O, 1, 2, 3, 4, 5, or 6; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof or isotopic variants thereof, stereoisomers or tautomers thereof.
  • the present invention relates to compounds having antiinflammatory properties, according to formulae Ia, Ib, Ic, Id, Ie, If, Ig, or Ih:
  • X represents a carbon-carbon bonded nitrogen-containing heterocycloalkyl group
  • B represents substituted or unsubstituted CpC ⁇ alkyl, or CpC ⁇ haloalkyl; or B represents substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkylalkyl or heterocycloalkylalkyl; or B represents substituted or unsubstituted aralkyl, aryl or heteroaryl; or with respect to a compound according to the formulae Ia or Ig, B further includes H, NO 2 , Ci-C 6 alkyl, halo, -CO-aryl, -CO-heteroaryl, -CON(R 4 )-aryl, or CO-N(R 4 )- heteroaryl;
  • Y represents a bond, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; the group B-(CH 2 )n-, B-CO-, B-N(R 10 )CO-, B-SO 2 -, B-OCO-, B-N(R 10 )SO 2 -, B-Y- or B- NR 10 -D(R 9 )- is linked to X via a nitrogen atom within the X group;
  • D represents CH or N, with the proviso that when D represents CH, R 9 represents -NO 2 and when D represents N, R 9 represents CN;
  • R 1 represents H, CpC 6 alkyl, (CH 2 )n-aryl, cycloalkyl or - CpC 6 alkyl-cycloalkyl group, each of which may optionally be substituted with one or more groups selected from halogen, CN, CF 3 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , CpC 6 alkyl, CpC 6 alkoxy, COR 4 , CO 2 R 4 , or SO 2 R 4 ;
  • R 2 represents H, CpC 6 alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, (CH 2 )n-aryl, or a heteroaryl group, each of which may optionally be substituted with one or more groups selected from halogen, CN, NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , CpC 6 alkyl, CpC 6 haloalkyl, CpC 6 alkoxy, CpC 6 haloalkoxy, COR 4 , CO 2 R 4 , or SO 2 R 4 ;
  • R 3 represents H, halogen, CpC 6 alkyl, cycloalkyl, (CH 2 )n-aryl, aryl, or a heteroaryl group, each of which may optionally be substituted with one or more groups selected from halogen,
  • CN NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , CpC 6 alkyl, CpC 6 haloalkyl, CpC 6 alkoxy, CpC 6 haloalkoxy, COR 4 , CO 2 R 4 , or SO 2 R 4 ;
  • R 4 represents H, CpC 6 alkyl, halo CpC 6 alkyl, cycloalkyl, or heterocycloalkyl;
  • R 5 represents H, CpC 6 alkyl, or cycloalkyl
  • R 9 represents CN or NO 2 ;
  • R 10 represents H or CpC 6 alkyl; and each "n” independently represents O, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof or isotopic variants thereof, stereoisomers or tautomers thereof.
  • the compound is according to formula Ia.
  • the compound is according to formula Ib.
  • the compound is according to formula Ic.
  • the compound is according to formula If.
  • the compound is according to formula Ih.
  • B is substituted aralkyl, aryl or heteroaryl and the substitution is selected from halogen, CN, CF 3 , NR 4 R 5 , NHCOR 4 ,
  • B is substituted aralkyl, aryl or heteroaryl and the substitution is selected from substituted or unsubstituted aryl, heterocycloalkyl and heterocycloalkylalkyl.
  • X is selected from piperidine, pyrrolidine and azetidine. In a particular embodiment X is piperidine or azetidine.
  • n is 0 and B is other than NO 2 or halo.
  • n is 0 and B is substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
  • n is 0 and B is substituted or unsubstituted aralkyl, aryl or heteroaryl.
  • n 0 and B is Ci-
  • Y is a bond
  • B is other than NO 2 or halo.
  • the compound is according to formulae Ha, lib, Hc, Hd, He, Hf, Hg, or Hh:
  • R 10 is H or CpC ⁇ alkyl; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof or isotopic variants thereof, stereoisomers or tautomers thereof.
  • R 10 is H or Me. In a particular embodiment R 10 is H.
  • the compound is according to formulae Ilia, HIb, UIc, HId, IHe, IHf, IHg, or IHh:
  • R 10 is H or Me; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof or isotopic variants thereof, stereoisomers or tautomers thereof.
  • R 10 is H or Me.
  • R 10 is H.
  • R is Ci-Ce alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl.
  • R is Me, i-Pr, t-Bu, cyclohexyl, cyclopentyl, cyclobutyl, phenyl, 4-fluorophenyl, pyridyl or pyrrolidinyl.
  • R is t-Bu, cyclohexyl cyclobutyl, phenyl or 4-fluorophenyl.
  • R 3 is H or CpC 6 alkyl.
  • R 3 is H or Me.
  • R is H
  • Ci-Ce haloalkyl Ci-Ce haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl, heteroarylalkyl, or heterocycloalkyl.
  • B is unsubstituted or substituted aryl.
  • B is phenyl unsubstituted or substituted with one or more groups selected from halogen, CN, NR 4 R 5 , NR 5 COR 4 ,
  • B is phenyl substituted with one or more groups selected from Me, Et, i-Pr, n-Bu, t-Bu, F, Cl, CF 3 , OMe, OEt,
  • OCF 3 OCHF 2 , CN, NO 2 , CO 2 Me, NHAc, NH 2 , NMe 2 , COMe, NHSO 2 Me, NHSO 2 Et, and NHSO 2 -
  • B is phenyl substituted with substituted or unsubstituted aryl, cycloalkyl, heterocycloalkyl or heteroaryl.
  • B is phenyl substituted with piperazin-1-yl, N-methylpiperazin-1-yl, N-isopropylpiperazin-1-yl, morpholin-1-yl, piperidin-1-yl, pyrrolidin-1-yl, or morpholin-1-ylmethyl.
  • B is substituted or unsubstituted heteroaryl.
  • B is benzo[l,3]dioxalyl, benzimidazol-2-yl, benzthiazol-2-yl, benzoxazol-2-yl, oxazol-2-yl, oxadiazolyl, thiazol-2-yl, imidazol-2-yl, or tetrazolyl; unsubstituted or substituted with one or more groups selected from alkyl, haloalkyl, halo, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylphenyl ,aryl and heteroaryl.
  • n is 0 and B is other than NO 2 or halo.
  • n is 0 and B is substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
  • n is 0
  • B is substituted or unsubstituted aralkyl, aryl or heteroaryl.
  • n is 0
  • B is Ci-C 6 alkyl, -CO-aryl, -CO-heteroaryl, -CON(R 4 )-aryl, or -CO-N(R 4 )-heteroaryl.
  • Y is a bond
  • B is other than NO 2 or halo.
  • the group B-Y- is selected from wherein each one of R 8c or R 8d is independently selected from H, halogen, CN, -NO 2 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , COR 4 , CO 2 R 4 , and SO 2 R 4 , or each one of R 8c or R 8d is independently selected from Ci-Ce alkyl, Ci-C ⁇ haloalkyl, Ci- C 6 alkoxy, and CpC 6 haloalkoxy, or each one of R 8c or R 8d is independently selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl and heteroaryl;
  • R 8e is selected from H, CpC 6 alkyl, and halo CpC 6 alkyl; or
  • R , 8 ⁇ e e is selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl or heteroaryl; and each of subscript ml and m2 is independently selected from O, 1 and 2.
  • B-Y- is as described above and each of R 8c or R 8d is independently selected from H, Me, t-Bu, F, Cl, CF 3 ; and each of subscript ml and m2 is independently selected from 1 and 2.
  • the group B-Y- is as described above and each of R 8c or R 8d is independently selected from H, Ph, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, N-Me-piperazin-1-yl, N-i-Pr-piperazin-1-yl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • the group B-Y- is as described above and each of R 8c or R 8d is independently selected from H, Ph, morpholinylmethyl, piperidinylmethyl, piperazinylmethyl, N-Me-piperazinylmethyl, N-i-Pr- piperazinylmethyl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • the group B-Y- is as described above and each of R 8c or R 8d is independently selected from H, Ph, morpholinylphenyl, piperidinylphenyl, piperazinylphenyl, N-Me-piperazinylphenyl, and N-i-Pr- piperazinylphenyl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • the group B-Y- is selected from
  • the compound is according to formula
  • R 10 is H.
  • the compound is according to formulae IVa, IVb, IVc or IVd:
  • R 8a and R 8b are independently selected from H, Ci-C 6 alkyl, halo, CN, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl.
  • each of R 8a and R 8b may be selected from H, CpC 6 alkyl, halo, CN, CpC 6 alkoxy, CpC 6 haloalkyl, CpC 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl and heterocycloalkylalkyl.
  • the compound is according to formulae Va, Vb, Vc or Vd:
  • R 8a and R 8b are independently selected from H, CpC 6 alkyl, halo, CN, CpC 6 alkoxy, CpC 6 haloalkyl, CpC 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl.
  • R 8a is H, Me,
  • R 8a is H
  • R 8b is H, Me, Cl, F, NMe 2 , OMe, i-Pr, t-Bu, OCF 3 , CF 3 , CN, morpholin-1-yl, piperazin-1-yl, N- methylpiperazin- 1 -yl or N-isopropylpiperazin- 1 -yl.
  • B is selected from Ci-Ce alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and aralkyl.
  • B is selected from Ci-C ⁇ alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and aralkyl.
  • B is selected from t-Bu, i-Pr, n-Bu, cyclohexyl, cyclopentyl, cyclohexylmethyl, cyclopentylmethyl, piperidinyl, and benzyl.
  • each one of R 8c or R 8d is independently selected from H, halogen, CN, -NO 2 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , COR 4 , CO 2 R 4 , and SO 2 R 4 , or each one of R 8c or R 8d is independently selected from Ci-Ce alkyl, halo Ci-C ⁇ alkyl, CpC 6 alkoxy, and halo CpC 6 alkoxy, or each one of R 8c or R 8d is independently selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl and heteroaryl;
  • R 8e is selected from H, CpC 6 alkyl, and CpC 6 haloalkyl; or
  • R 8e is selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl or heteroaryl; and each of subscript ml and m2 is independently selected from O, 1 and 2.
  • B is as described above and each of R 8c or R 8d is independently selected from H, Me, t-Bu, F, Cl or CF 3 ; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, N-Me-piperazin-1-yl, N-i-Pr-piperazin-1-yl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholinylmethyl, piperidinylmethyl, piperazinylmethyl, N-Me-piperazinylmethyl, and N-i-Pr-piperazinylmethyl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • R 8c or R 8d is independently selected from H, Ph, morpholinylphenyl, piperidinylphenyl, piperazinylphenyl, N-Me-piperazinylphenyl, and N-i-Pr-piperazinylphenyl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • the compound is according to formula
  • the compound is according to formulae Villa, VIIIb, VIIIc or VIIId:
  • R 8a and R 8b are independently selected from H, CpC 6 alkyl, halo, CN, CpC 6 alkoxy, CpC 6 haloalkyl, Ci-Ce haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl.
  • R 8a and R 8b are independently selected from H, Ci-C 6 alkyl, halo, CN, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl.
  • R 8a is H, Me
  • R 8a is H; and R 8b is H, Me, Cl, F, NMe 2 , OMe, i-Pr, t-Bu, OCF 3 , CF 3 , CN, morpholin-1-yl, piperazin-1-yl, N- methylpiperazin-1-yl or N-isopropylpiperazin-1-yl.
  • R 8a is H and R 8b is H, F,
  • the compound is according to formulae Xa, Xb, Xc or Xd:
  • B is selected from Ci-C 6 alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and aralkyl.
  • the compound is according to formulae XIa, XIb, XIc or XId:
  • B is selected from Ci-Ce alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and aralkyl.
  • B is selected from t-Bu, i-Pr, n-Bu, cyclohexyl, cyclopentyl, cyclohexylmethyl, cyclopentylmethyl, piperidinyl and benzyl.
  • R 8 ' wherein each one of R c or R is independently selected from H, halogen, CN, -NO 2 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , COR 4 , CO 2 R 4 , and SO 2 R 4 , or each one of R 8c or R 8d is independently selected from CpC 6 alkyl, CpC 6 haloalkyl, Cp C 6 alkoxy, and CpC 6 haloalkoxy, or each one of R 8c or R 8d is independently selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl and heteroaryl;
  • R 8e is selected from H, CpC 6 alkyl, and CpC 6 haloalkyl; or
  • R 8e is selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl or heteroaryl; and each of subscript ml and m2 is independently selected from 0, 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Me, t-Bu, F, Cl, and CF 3 ; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, N-Me-piperazin-1-yl, N-i-Pr-piperazin-1-yl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholinylmethyl, piperidinylmethyl, piperazinylmethyl, N-Me-piperazinylmethyl, N-i-Pr-piperazinylmethyl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholinylphenyl, piperidinylphenyl, piperazinylphenyl, N-Me-piperazinylphenyl, and N-i-Pr-piperazinylphenyl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • the compound is according to formula
  • the compound is according to formulae XIIa, XIIb, XIIc or XIId: wherein R 8a and R 8b are independently selected from H, Ci-C 6 alkyl, halo, CN, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl.
  • R 8a and R 8b are independently selected from H, Ci-C 6 alkyl, halo, CN, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl.
  • R 8a and R 8b are independently selected from H, CpC 6 alkyl, halo, CN, CpC 6 alkoxy, CpC 6 haloalkyl, Ci-C 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl.
  • R 8a is H, Me,
  • R 8a is H; and R 8b is H, Me, Cl, F, NMe2, OMe, i-Pr, t-Bu, OCF3, CF3, CN, morpholin-1-yl, piperazin-1-yl, N- methylpiperazin- 1 -yl or N-isopropylpiperazin- 1 -yl.
  • the compound is according to formulae XIVa, XIVb, XIVc or XIVd:
  • B is selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and aralkyl.
  • the compound is according to formulae XVa, XVb, XVc or XVd:
  • B is selected from Ci-C ⁇ alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and aralkyl.
  • B is selected from t-Bu, i-Pr, n-Bu, cyclohexyl, cyclopentyl, cyclohexylmethyl, cyclopentylmethyl, piperidinyl and benzyl.
  • each one of R 8c or R 8d is independently selected from H, halogen, CN, -NO 2 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , COR 4 , CO 2 R 4 and SO 2 R 4 , or each one of R 8c or R 8d is independently selected from CpC 6 alkyl, CpC 6 haloalkyl, Ci- Ce alkoxy, and Ci-Ce haloalkoxy, or each one of R 8c or R 8d is independently selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl and heteroaryl; R 8e is selected from H, Ci-C 6 alkyl, and Ci-C 6 haloalkyl; or R 8e is selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl,
  • each of R 8c or R 8d is independently selected from H, Me, t-Bu, F, Cl, and CF 3 ; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, N-Me-piperazin-1-yl, N-i-Pr-piperazin-1-yl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholinylmethyl, piperidinylmethyl, piperazinylmethyl, N-Me-piperazinylmethyl, N-i-Pr-piperazinylmethyl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholinylphenyl, piperidinylphenyl, piperazinylphenyl, N-Me-piperazinylphenyl, and N-i-Pr-piperazinylphenyl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • the compound is according to formula
  • the compound is according to formulae XVIa, XVIb, XVIc or XVId:
  • R 8a and R 8b are independently selected from H, Ci-C 6 alkyl, halo, CN, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl.
  • the compound is according to formulae XVIIa, XVIIb, XVIIc or XVIId:
  • R 8a and R 8b are independently selected from H, alkyl, halo, CN, alkoxy, haloalkyl, haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl.
  • R 8a is H
  • R 8a is
  • R 8b is H, Me, Cl, F, NMe 2 , OMe, i-Pr, t-Bu, OCF 3 , CF 3 , CN, morpholin-1-yl, piperazin-1-yl, N- methylpiperazin- 1 -yl or N-isopropylpiperazin- 1 -yl.
  • the compound is according to formulae XVIIIa, XVIIIb, XVIIIc or XVIIId:
  • the compound is according to formulae XIXa, XIXb, XIXc or XIXd:
  • B is selected from CpC ⁇ alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and aralkyl.
  • B is selected from t-Bu, i-Pr, n-Bu, cyclohexyl, cyclopentyl, cyclohexylmethyl, cyclopentylmethyl, piperidinyl, and benzyl.
  • each one of R 8c or R 8d is independently selected from H, halogen, CN, -NO 2 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , COR 4 , CO 2 R 4 and SO 2 R 4 , or each one of R 8c or R 8d is independently selected from CpC 6 alkyl, CpC 6 haloalkyl, Ci- C 6 alkoxy, and CpC 6 haloalkoxy, or each one of R 8c or R 8d is independently selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl and heteroaryl;
  • R 8e is selected from H, Ci-C 6 alkyl, and Ci-C 6 haloalkyl; or
  • R 8e is selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl or heteroaryl; and each of subscript ml and m2 is independently selected from O, 1 and 2..
  • B is as described above and each of R 8c or R 8d is independently selected from H, Me, t-Bu, F, Cl, and CF 3 ; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, N-Me-piperazin-1-yl, N-i-Pr-piperazin-1-yl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholinylmethyl, piperidinylmethyl, piperazinylmethyl, N-Me-piperazinylmethyl, N-i-Pr-piperazinylmethyl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholinylphenyl, piperidinylphenyl, piperazinylphenyl, N-Me-piperazinylphenyl, and N-i-Pr-piperazinylphenyl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • the compound is according to formula
  • Y is a bond.
  • the compound is according to formulae XXa, XXb, XXc or XXd:
  • R 8a and R 8b are independently selected from H, Ci-C 6 alkyl, halo, CN, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl.
  • the compound is according to formulae XXIa, XXIb, XXIc or XXId:
  • R 8a and R 8b are independently selected from H, CpC 6 alkyl, halo, CN, CpC 6 alkoxy, CpC 6 haloalkyl, Ci-C 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl.
  • R 8a is H, Me,
  • R 8a is H; and R 8b is H, Me, Cl, F, NMe 2 , OMe, i-Pr, t-Bu, OCF 3 , CF 3 , CN, morpholin-1-yl, piperazin-1-yl, N- methylpiperazin- 1 -yl or N-isopropylpiperazin- 1 -yl.
  • the compound is according to formulae XXIIa, XXIIb, XXIIc or XXIId:
  • B is selected from Ci-Ce alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, heteroaryl and aralkyl.
  • the compound is according to formulae XXIIIa, XXIIIb, XXIIIc or XXIIId:
  • B is selected from Ci-C ⁇ alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, heteroaryl and aralkyl.
  • B is selected from t-Bu, i-Pr, n-Bu, cyclohexyl, cyclopentyl, cyclohexylmethyl, cyclopentylmethyl, piperidinyl, and benzyl.
  • Y is substituted or unsubstituted aryl.
  • Y is substituted or unsubstituted heteroaryl.
  • the compound is according to formulae XXIVa, XXIVb, XXIVc or XXIVd:
  • Y is substituted or unsubstituted heteroaryl
  • B is selected from H, CpC 6 alkyl, CpC 6 haloalkyl, halo, CN, NO 2 , aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylphenyl and aralkyl.
  • the compound is according to formulae XXVa, XXVb, XXVc or XXVd:
  • Y is substituted or unsubstituted heteroaryl
  • B is selected from H, CpC 6 alkyl, CpC 6 haloalkyl, halo, CN, NO 2 , aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylphenyl, and aralkyl.
  • Y is selected from pyridyl, pyrimidyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benz[l,3]dioxalyl, thiophenyl, pyrrolidinyl, furanyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, and tetrazolyl.
  • B is selected from H, Me, t-Bu, F, Cl, CF 3 , NO 2 , Ph, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, N-Me- piperazin-1-yl, N-i-Pr-piperazin-1-yl, morpholinylmethyl, piperidinylmethyl, piperazinylmethyl, N- Me-piperazinylmethyl, N-i-Pr-piperazinylmethyl, morpholinylphenyl, piperidinylphenyl, piperazinylphenyl, N-Me-piperazinylphenyl, and N-i-Pr-piperazinylphenyl.
  • B-Y- is selected from
  • each one of R 8c or R 8d is independently selected from H, halogen, CN, -NO 2 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , COR 4 , CO 2 R 4 , and SO 2 R 4 , or each one of R 8c or R 8d is independently selected from CpC 6 alkyl, CpC 6 haloalkyl, Ci- Ce alkoxy, and Ci-Ce haloalkoxy, or each one of R 8c or R 8d is independently selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl and heteroaryl;
  • R 8e is selected from H, Ci-C 6 alkyl, and Ci-C 6 haloalkyl; or
  • R 8e is selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl or heteroaryl; and each of subscript ml and m2 is independently selected from 0, 1 and 2..
  • B-Y- is as described above and each of R 8c or R 8d is independently selected from H, Me, t-Bu, F, Cl, CF 3 ; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, N-Me-piperazin-1-yl, N-i-Pr-piperazin-1-yl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholinylmethyl, piperidinylmethyl, piperazinylmethyl, N-Me-piperazinylmethyl, N-i-Pr- piperazinylmethyl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • the group B-Y- is as described above and each of R 8c or R 8d is independently selected from H, Ph, morpholinylphenyl, piperidinylphenyl, piperazinylphenyl, N-Me-piperazinylphenyl, and N-i-Pr- piperazinylphenyl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • the group B-Y- is selected from
  • B is selected from t-Bu, i-Pr, n-Bu, cyclohexyl, cyclopentyl, cyclohexylmethyl, cyclopentylmethyl, piperidinyl, benzo[l,3]dioxalyl, benzimidazol-2-yl, methylbenzimidazol-2-yl, trifluoromethylbenzimidazol-2-yl, and benzyl.
  • B is benzimidazol-2-yl, methylbenzimidazol-2-yl, or trifluoromethylbenzimidazol-2-yl.
  • B is benzimidazol-2-yl, or trifluoromethylbenzimidazol-2-yl.
  • B is benzthiazol-2-yl or benzoxazol-2-yl.
  • B is oxazol-2-yl, oxadiazolyl, thiazol-2-yl, imidazol-2-yl, or tetrazolyl.
  • B is substituted oxazol-2-yl, substituted oxadiazolyl, substituted thiazol-2-yl, substituted imidazol-2-yl, or substituted tetrazolyl and the substitution is selected from methyl, t-Bu, phenyl, morpholinomethyl, piperidinomethyl, or alkylpiperazinomethyl.
  • B is pyridyl.
  • the compound is according to formula
  • R 10 is H.
  • the compound is according to formulae formulae XXVIa, XXVIb, XXVIc or XXVId:
  • R 8a and R 8b are independently selected from H, Ci-C 6 alkyl, halo, CN, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl; and the group D-R 9 is N-CN or CH-NO 2 .
  • the compound is according to formulae XXVIIa, XXVIIb, XXVIIc or XXVIId:
  • R 8a and R 8b are independently selected from H, Ci-C 6 alkyl, halo, CN, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl; and the group D-R 9 is N-CN or CH-NO 2 .
  • R 8a is
  • R 8b is H, Me, Cl or F.
  • R 8a is H; and R 8b is H, Me, Cl, F, NMe 2 , OMe, i-Pr, t-Bu, OCF 3 , CF 3 , CN, morpholin-1-yl, piperazin-1-yl,
  • the compound is according to formulae XXVIIIa, XXVIIIb, XXVIIIc or XXVIIId:
  • R 8a and R 8b are independently selected from H, CpC 6 alkyl, halo, CN, CpC 6 alkoxy, Ci-Ce haloalkyl, Ci-C ⁇ haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl; and the group D-R 9 is N-CN or CH-NO 2 .
  • the compound is according to formulae XXIXa, XXIXb, XXIXc or XXIXd:
  • R 8a and R 8b are independently selected from H, CpC 6 alkyl, halo, CN, CpC 6 alkoxy,
  • B is selected from t-Bu, i-Pr, n-Bu, cyclohexyl, cyclopentyl, cyclohexylmethyl, cyclopentylmethyl, piperidinyl, and benzyl.
  • each one of R 8c or R 8d is independently selected from H, halogen, CN, -NO 2 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , COR 4 , CO 2 R 4 and SO 2 R 4 , or each one of R 8c or R 8d is independently selected from Ci-Ce alkyl, Ci-C ⁇ haloalkyl, Ci- C 6 alkoxy, and CpC 6 haloalkoxy, or each one of R 8c or R 8d is independently selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl and heteroaryl;
  • R 8e is selected from H, Ci-C 6 alkyl, and Ci-C 6 haloalkyl; or
  • R 8e is selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl or heteroaryl; and each of subscript ml and m2 is independently selected from O, 1 and 2..
  • each of R 8c or R 8d is independently selected from H, Me, t-Bu, F, Cl, and CF 3 ; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, N-Me-piperazin-1-yl, N-i-Pr-piperazin-1-yl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholinylmethyl, piperidinylmethyl, piperazinylmethyl, N-Me-piperazinylmethyl, N-i-Pr-piperazinylmethyl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • each of R 8c or R 8d is independently selected from H, Ph, morpholinylphenyl, piperidinylphenyl, piperazinylphenyl, N-Me-piperazinylphenyl, and N-i-Pr-piperazinylphenyl; and each of subscript ml and m2 is independently selected from 1 and 2.
  • the compound is selected from:
  • the compound is selected from all compounds of the invention exemplified specifically herein.
  • a compound for use according to the invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. It will be understood by a person of skill in the art that the present invention includes both the racemic mixture and each enantiomer in isolated form.
  • a compound according to an embodiment of the invention may be in trans or cis form.
  • the present invention also extends to a prodrug of a compound according to an embodiment of the invention such as an ester or amide thereof.
  • a prodrug is a compound that may be converted under physiological conditions or by solvolysis to a compound according to an embodiment of the invention or to a pharmaceutically acceptable salt of a compound according to an embodiment of the invention.
  • a prodrug may be inactive when administered to a subject but is converted in vivo to an active compound of the invention.
  • 'Pharmaceutically acceptable prodrugs' as used herein refers to those prodrugs of the compounds useful in the present invention, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients with undue toxicity, irritation, allergic response commensurate with a reasonable benefit/risk ratio, and effective for their intended use of the compounds of the invention.
  • 'prodrug' means a compound that is transformed in vivo to yield an effective compound useful in the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • the transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • the compounds bearing metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group, thus, such compounds act as prodrugs.
  • a thorough discussion is provided in Design of Prodrugs, H. Bundgard, ed., Elsevier (1985); Methods in Enzymology; K.
  • compositions suitable for administration typically comprise at least one compound of the invention and at least one pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include solid carriers such as lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin, acacia or the like; and liquids such as vegetable oils, arachis oil and sterile water, or the like, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, 'chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum mono stearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile powders for the preparation of sterile injectable solutions the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • compositions can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • suppositories e.g., with conventional suppository bases such as cocoa butter and other glycerides
  • retention enemas for rectal delivery.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • a compound according to an embodiment of the invention may be provided as a salt, preferably as a pharmaceutically acceptable salt of compounds of formula I or Formulae Ia-Ih.
  • pharmaceutically acceptable salts of these compounds include those derived from organic acids such as acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulphonic acid, benzenesulphonic acid and />-toluenesulphonic acid, mineral acids such as hydrochloric and sulphuric acid and the like, giving methanesulphonate, benzenesulphonate, p- toluenesulphonate, hydrochloride and sulphate, and the like, respectively or those derived from bases such as organic and inorganic bases.
  • suitable inorganic bases for the formation of salts of compounds for this invention include the hydroxides, carbonates, and bicarbonates of ammonia, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc and the like. Salts can also be formed with suitable organic bases.
  • bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases which are nontoxic and strong enough to form salts.
  • Such organic bases are already well known in the art and may include amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; N-methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl) aminomethane; and the like.
  • amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; N-methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzy
  • Salts of compounds according to an embodiment of the invention may be prepared in a conventional manner using methods well known in the art.
  • Acid addition salts of said basic compounds may be prepared by dissolving the free base compounds according to the first or second aspects of the invention in aqueous or aqueous alcohol solution or other suitable solvents containing the required acid.
  • a base salt of said compound may be prepared by reacting said compound with a suitable base. The acid or base salt may separate directly or can be obtained by concentrating the solution e.g. by evaporation.
  • the compounds of this invention may also exist in solvated or hydrated forms.
  • a compound of the invention is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 240-270 mg tablets (80-90 mg of active amide compound per tablet) in a tablet press.
  • a compound of the invention is admixed as a dry powder with a starch diluent in an approximate 1 :1 weight ratio.
  • the mixture is filled into 250 mg capsules (125 mg of active amide compound per capsule).
  • a compound of the invention (125 mg), sucrose (1.75 g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 mL.
  • a compound of the invention is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 450-900 mg tablets (150-300 mg of active amide compound) in a tablet press.
  • a compound of the invention is dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) are melted at about 75°C and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) is added and the resulting mixture is stirred until it congeals.
  • the present invention relates also to a method of treatment or prevention of osteoarthritis, which comprises administering to a subject in need thereof, a therapeutically effective amount of compound of the invention.
  • the present invention relates also to a method of treatment or prevention of osteoarthritis, which comprises administering to a subject in need thereof, a therapeutically effective amount of an inhibitor of PDElA according to Formula I.
  • the present invention relates also to a method of treatment or prevention of osteoarthritis, which comprises administering to a subject in need thereof, a therapeutically effective amount of an inhibitor of PDElA according to Formulae Ia-Ih.
  • Another aspect of the present method invention relates to a method of treatment or prophylaxis of a condition characterized by abnormal PDElA activity, which comprises administering a therapeutically effective amount of a PDElA inhibiting compound according to Formula I or Formulae Ia-Ih.
  • a further aspect of the present method invention is a method of treatment or prophylaxis of a disease involving degradation of cartilage, which comprises administering a therapeutically effective a compound according to Formula I or Formulae Ia-Ih.
  • a special embodiment of the present method invention is a method of treatment or prevention of OA, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to Formula I or Formulae Ia-Ih.
  • This invention also relates to the use of the present compounds in the manufacture of a medicament for treatment or prophylaxis of a condition prevented, ameliorated or eliminated by administration of an inhibitor of PDElA which is a compound of the invention, or a condition selected from diseases involving inflammation, most preferably for the treatment of diseases selected from osteoarthritis, rheumatoid arthritis and osteoporosis.
  • an inhibitor of PDElA which is a compound of the invention, or a condition selected from diseases involving inflammation, most preferably for the treatment of diseases selected from osteoarthritis, rheumatoid arthritis and osteoporosis.
  • Administration of the compound of the present invention to the subject patient includes both self-administration and administration by another person.
  • the patient may be in need of treatment for an existing disease or medical condition, or may desire prophylactic treatment to prevent or reduce the risk for diseases and medical conditions affected by a disturbance in bone metabolism.
  • the compound of the present invention may be delivered to the subject patient orally, transdermally, via inhalation, injection, nasally, rectally or via a sustained release formulation.
  • a preferred regimen of the present method comprises the administration to a subject in suffering from a disease condition characterized by a disturbance in bone and/or cartilage metabolism., of an effective PDEIA- inhibiting amount of a compound of the present invention for a period of time sufficient to reduce the abnormal levels of bone and/or cartilage degradation in the patient, and preferably terminate, the self-perpetuating processes responsible for said degradation.
  • a special embodiment of the method comprises administering of an effective PDElA inhibiting amount of a compound of the present invention to a subject patient suffering from or susceptible to the development of osteoarthritis, for a period of time sufficient to reduce or prevent, respectively, collagen and bone degradation in the joints of said patient, and preferably terminate, the self- perpetuating processes responsible for said degradation.
  • Toxicity and therapeutic efficacy of such compounds can be determined by Standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 ZED 50 .
  • Compounds that exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC 50 i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography.
  • a preferred therapeutically effective amount of the compound of the present invention to administer to a subject patient is about 0.1 mg/kg to about 10 mg/kg administered from once to three times a day.
  • an effective regimen of the present method may administer about 5 mg to about 1000 mg of said compound of the present invention from once to three times a day.
  • the specific dose level for any particular subject patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular inflammatory condition. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • the compounds of this invention When used to prevent the onset of a condition related to bone and/or cartilage degradation the compounds of this invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those who have been identified by genetic testing or screening to be particularly susceptible to developing said condition.
  • the compounds of this invention can be administered as the sole active agent or they can be administered in combination with other agents, including other compounds that demonstrate the same or a similar therapeutic activity and that are determined to safe and efficacious for such combined administration.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; however, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [00261] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
  • a compound according to the present invention can be produced according to the following scheme. [00264] 1.1. General Synthetic Route
  • Step 2 5-Amino-l -cyclohexyl-lH-pyrazole-4-carboxylic acid amide
  • Step 2 5-Amino-l-t ⁇ rf-butyl -3-methyl-lH-pyrazole-4-carboxylic acid amide
  • Sodium hydroxide solution (IN, 26 mL) was added followed by dropwise addition of hydrogen peroxide solution (35 wt. % in water, 10.5 mL, 118.6 mmol).
  • the reaction was maintained at 0 0 C for 10 min then allowed to warm to room temperature. An exotherm was observed when the reaction reached the ambient temperature. Once the reaction had cooled to room temperature, EtOH was removed under reduced pressure and the residue was diluted with water (100 mL) causing the formation of a precipitate. The precipitate was collected by filtration, rinsed with water and dried. The filtrate was extracted with EtOAc (3 x 150 mL). The combined organic phases were washed with water (100 mL) then with brine (2 x 100 mL), dried (MgSO4) and concentrated to dryness.
  • l-Benzhydrylazetidine-3-carboxylic acid (16.0 g, 59.8 mmol) was added portionwise to thionyl chloride (50 mL), and the resulting mixture was stirred at room temperature for 4 h. Thionyl chloride was then removed under reduced pressure. The residue was triturated with THF (50 ml) which was then evaporated. l-Benzhydrylazetidine-3-carbonyl chloride hydrochloride (19.3 g, 100 %) was isolated as a beige solid, and used without further purification.
  • Step 2 6-(l-Benzhydrylazetidin-3-yl)-l-t ⁇ rf-butyl-3-methyl-l,5-dihydropyrazolo[3,4-d] pyrimidin-4-one
  • Step 3 6-Azetidin-3-yl-l-t ⁇ rf-butyl-3-methyl-l,5-dihydro-pyrazolo[3,4- ⁇ /]pyrimidin-4-one hydrochloride
  • Step 2 l-Cyclohexyl-3-methyl-6-piperidin-3-yl-l,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one hydrochloride
  • Examples 3-114 listed in Table 2 were made from Descriptions 3-14 according to the procedure described in Example 1, using the appropriate isocyanate, isothiocyanate, acid chloride or sulfonyl chloride or according to the procedure described in Example 2 using the appropriate amine.
  • Examples 117-124 in Table 3 were made according to the procedure of Example 115 using the appropriate chloroformate or according to the procedure of Example 116 using the appropriate alcohol.
  • Example 125 l-Cvclohexyl- ⁇ -d-dH-benzoff/limidazol-l-vDazetidin-S-vD-lH-pyrazolofS ⁇ - ⁇ j ⁇ pyrimidin-4-(5H)-one
  • Examples 126-144 in Table 4 were made from the appropriate chloride, bromide or sulfonic acid according to the procedure of Example 125.
  • Example 145 l-Cvclohexyl-6-(l-(4-(morpholinosulfonyl)phenyl)azetidin-3-yl)-lH-pyrazolo[3,4- dl pyrimidin-4(5H)-one
  • Example 155 l-Cvclohexyl-6-[l-(4-morpholin-4-ylmethyl-phenyl)-azetidin-3-yll-l,5-dihvdro- pyrazolo[3,4- ⁇ i ⁇ pyrimidin-4-one
  • Step 1 4-[3-(l-Cyclohexyl-4-oxo-4,5-dihydro-lH-pyrazolo[3,4- ⁇ /]pyrimidin-6-yl)-azetidin-l-yl]- benzaldehyde
  • Step 2 l-Cyclohexyl-6-[l-(4-morpholin-4-ylmethyl-phenyl)-azetidin-3-yl]-l,5-dihydro- pyrazolo[3,4-rf]pyrimidin-4-one
  • Example 156 l-Cvclohexyl-6-(l-(2-(morpholinomethyl)phenyl)azetidin-3-yl)-lH-pyrazolo [3,4- dl pyrimidin-4(5H)-one
  • Step 1 ⁇ -Cl-CyclohexyM-oxo ⁇ S-dihydro-lH-pyrazoloP ⁇ - ⁇ pyrimidin- ⁇ -yl) azetidine-1- carbothioyl]benzamide
  • Step 2 3-(l-Cyclohexyl-4-oxo-4,5-dihydro-lH-pyrazolo[3,4-rf]pyrimidin-6-yl)-azetidine-l- carbothioic acid amide
  • Step 3 6-(l-(4-tert-Butylthiazol-2-yl)azetidin-3-yl)-l-cyclohexyl-lH-pyrazolo[3,4-rf]pyrimidi-4- (5H)-one [00307]
  • Example 158 l-Cvclohexyl-e-d-CS-phenvMH-l ⁇ -triazol-S-vDazetidin-S-vD-lH-pyrazolofS ⁇ -
  • Step 1 l-Cyclohexyl-6-(l-(4-bromothiazol-2-yl)azetidin-3-yl)-lH-pyrazolo[3,4-rf]pyrimidi-4- (5H)-one
  • Step 2 l-Cyclohexyl-6-(l-(4-phenylthiazol-2-yl)azetidin-3-yl)-lH-pyrazolo[3,4-rf]pyrimidi-4- (5H)-one.
  • Example 160 l-Cvclohexyl-6-(l-(5-phenylthiazol-2-yl)azetidin-3-yl)-lH-pyrazolo[3,4-
  • Example 161 l-Cvclohexyl-6-(l-(4-(4-(4-isopropylpiperazin-l-yl)phenyl)thiazol-2-yl)azetidin-3- vD-lH-pyrazolo [3,4- ⁇ j ⁇ pyrimidi-4-(5H)-one
  • Example 162 l-Cvclohexyl-6-(l-(5-morpholin-4-ylmethyl-4-phenylthiazol-2-yl)azetidin-3-yl)- lH-pyrazolo[3,4- ⁇ i ⁇ pyrimidi-4-(5H)-one
  • Phosphoras(III)oxychloride (8 ⁇ L, 0.08 mmol) was added under nitrogen to DMF (2 mL) at 0 0 C. The mixture was stirred at 0 0 C for 30 min then a solution of l-cyclohexyl-6-(l-(4- phenylthiazol-2-yl)azetidin-3-yl)-lH-pyrazolo[3,4-(/
  • Example 163 l-fer ⁇ Butyl-6-(l-pyridin-2-yl-azetidin-3-yl)-l,5-dihvdro-pyrazolo[3,4- ⁇ i ⁇ pyrimidin-4-one
  • Example 164 l-fer ⁇ -Butyl-6-[l-(4-morpholin-4-ylmethyl-phenyl)-azetidin-3-yll-l,5-dihvdro - pyrazolo[3,4- ⁇ i ⁇ pyrimidin-4-one
  • Examples 165-169 in Table 6 were made from commercially available aryl bromides according to the procedure of Example 163.
  • Example 170 3-(l-Cyclohexyl-3-methyl-4-oxo-4,5-dihydro-lH-pyrazolo[3,4-dlpyrimidin-6-yl)- N-(4-fluorobenzyl)-N-methylazetidine-l-carboxamide ⁇ N
  • Step 1 3-[(4-Fluorobenzyl)-methyl-carbamoyl]-l-methyl-3H-imidazol-l-ium iodide
  • Step 2 3-(l-Cyclohexyl-3-methyl-4-oxo-4,5-dihydro-lH-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4- fluorobenzyl)-N-methylazetidine-l-carboxamide
  • Example 172 6-(l-(Benzo[dlthiazol-2-ylmethyl)azetidin-3-yl)-l-cvclohexyl-lH-pyrazolo[3,4- dlpyrimidin-4(5H)-one
  • Example 173 1 H NMR (400MHz, CDCl 3 ): ⁇ 10.65 (IH, br s), 8.02 (IH, s), 7.93 (2H, m), 7.59 (IH, m), 7.49 (2H, m), 4.04 (2H, s), 3.81 (2H, m), 3.76 (2H, m), 3.61 (IH, m), 1.77 (9H, s). (MH + , m/z) 366.
  • Example 175 6-(l-((lH-Benzo[dlimidazol-2-yl)methyl)azetidin-3-yl)-l-fer ⁇ -butyl-lH- pyrazolo[3,4-dlpyrimidin-4(5H)-one
  • Step 2 N'-Cyano-3-(l-cyclohexyl-4-oxo-4,5-dihydro-lH-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4- fluorophenyl)azetidine-l-carboximidamide
  • Step 1 Phenyl N-cyano-3-(l-cyclohexyl-4-oxo-4,5-dihydro-lH-pyrazolo[3,4-d]pyrimidin-6- yl)azetidine-l-carbimidate
  • Step 2 N'-Cyano-3-(l-cyclohexyl-4-oxo-4,5-dihydro-lH-pyrazolo[3,4-d]pyrimidin-6-yl)-N- (cyclohexylmethyl)azetidine-l-carboximidamide
  • a mixture of the product of Step 1 (50 mg, 0.119 mmol) and cyclohexane methylamine (27 mg, 0.222 mmol) in 2-propanol (2 mL) was heated at 60 0 C for 20 h. A solid formed and was collected by filtration, washed with 2-propanol, then 40-60 0 C petrol, and dried in vacuo to give the title compound (31 mg).
  • Example 180 l-Cvclohexyl-6-(l-(l-(cvclohexylmethylamino)-2-nitrovinyl)azetidin-3-yl)-lH- pyrazolo[3,4-dlpyrimidin-4(5H)-one
  • Step 2 l-Cyclohexyl-6-(l-(l-(cyclohexylmethylamino)-2-nitrovinyl)azetidin-3-yl)-lH- pyrazolo[3,4-d]pyrimidin-4(5H)-one
  • Example 181 N-tl-P-ri-Cyclohexyl ⁇ -methyM-oxo ⁇ S-dihydro-lH-pyrazoloP. ⁇ -dlpyrimidin- 6-yl)-piperidine-l-carbonyllphenyl ⁇ -methanesulfonamide
  • Step 1 5-Amino-l-cyclohexyl-3-methyl-lH-pyrazole-4-carbonitrile
  • Step 5 l-(2-Methanesulfonylamino-benzoyl)-piperidine-3-carboxylic acid ethyl ester
  • Step 6 l-(2-Methanesulfonylamino-benzoyl)-piperidine-3-carboxylic acid
  • Step 7 l-(2-Methanesulfonylamino-benzoyl)-piperidine-3-carbonyl chloride
  • Step 8 5-Amino-l-cyclohexyl-3-methyl-lH-pyrazole-4-carboxylic acid amide
  • Step 9 l-(2-Methanesulfonylamino-benzoyl)-piperidine-3-carboxylic acid (4-carbamoyl-2- cyclohexyl-5-methyl-2 ⁇ -pyrazol-3-yl) amide
  • Step 10 N-Jl-P-Cl-Cyclohexyl-S-methyM-oxo ⁇ -dihydro-lH-pyrazoloIS ⁇ -dlpyrimidin- ⁇ -yl)- piperidine-l-carbonyl]phenyl ⁇ -methanesulfonamide
  • Example 182 3-(l-Cyclohexyl-4-oxo-4,5-dihvdro-lH-pyrazolo[3,4- ⁇ i ⁇ pyrimidin-6-yl)-azetidine-l- carboxylic acid piperidin-3-ylamide trifluoroacetate
  • Example 185 3-[l-(l-Isopropyl-azetidin-3-yl)-4-oxo-4,5-dihvdro-lH-pyrazolo[3,4- ⁇ pyrimidin-6- vU-azetidine-1-carboxylic acid (4-fluoro-phenyl)-amide
  • Step 2 ⁇ -(l-Benzhydryl-azetidin-3-ylidene)-hydrazinecarboxylic acid t ⁇ rf-butyl ester
  • l-Benzhydryl-azetidin-3-one (Step 1, 14.93 g, 63.00 mmol) and tert-butyl carbazate
  • Step 3 ⁇ '-(l-Benzhydryl-azetidin-S-ylJ-hydrazinecarboxylic acid tert-buty ⁇ ester
  • jV-(l-Benzhydryl-azetidin-3-ylidene)-hydrazinecarboxylic acid tert-butyl ester (18.66 g, 53.20 mmol) was dissolved in AcOH (150 mL) then sodium cyanoborohydride (3.31 g, 53.20 mmol) was added. The mixture was stirred for 5 h then concentrated in vacuo to about 1/3 volume. IM NaOH was added to pH 7 then the mixture was extracted with DCM (4 x 100 mL).
  • N'-(l-Benzhydryl-azetidin-3-yl)-hydrazinecarboxylic acid tert-butyl ester (2.83 mmol) was dissolved in 4M HCl in dioxane (10 mL). The mixture was stirred for 3 h then the solvents were removed in vacuo to give the product as a cream solid (2.70 mmol, 0.98 g, 95 %).
  • Step 5 5-Amino-l-(l-benzhydryl-azetidin-3-yl)-lH-pyrazole-4-carboxylic acid amide
  • (l-Benzhydryl-azetidin-3-yl)-hydrazine trihydrochloride (0.98 g, 2.70 mmol), ethoxymethylidene malononitrile (0.30 g, 2.45 mmol) and triethylamine (1.70 mL, 12.25 mmol) were mixed in EtOH (10 mL) and heated at 90 0 C for 16 h. The solvents were removed in vacuo and the residue was partitioned between water (10 mL) and EtOAc (10 mL).
  • the aqueous phase was extracted with EtOAc (3 x 10 mL) then the combined organics were dried over MgS ⁇ 4 and concentrated in vacuo to give a brown oil. This was dissolved and evaporated from EtOH (2 x) and diethyl ether to give the crude nitrile product as a brown foam. This foam was added portionwise to concentrated H 2 SO 4 (5 mL) at 0 0 C. The resulting mixture was stirred for 2 h then heated to 45 0 C for 1 hour. The cooled mixture was poured onto ice and basified with 0.88 ammonia solution (10 mL). The aqueous phase was extracted with EtOAc (4 x 30 mL).
  • Step 6 3-(5-Amino-4-carbamoyl-pyrazol-l-yl)-azetidine-l-carboxylic acid t ⁇ rf-butyl ester
  • 5-Amino-l-(l-benzhydryl-azetidin-3-yl)-lH-pyrazole-4-carboxylic acid amide (3.50 g, 10.09 mmol) was dissolved in EtOH (50 mL) and IM HCl (30 mL). Palladium hydroxide on carbon (20 % wt, 3.50 g) was added and the mixture was stirred under a hydrogen atmosphere (200 psi) for 6 h. The mixture was filtered and the solvent removed in vacuo.
  • Step 7 3-[6-(l-Benzhydryl-azetidin-3-yl)-4-oxo-4,5-dihydro-pyrazolo[3,4-rf]pyrimidin-l-yl]- azetidine-1-carboxylic acid tert-buty ⁇ ester
  • Step 8 6-(l-Benzhydryl-azetidin-3-yl)-l-(l-isopropyl-azetidin-3-yl)-l,5-dihydro-pyrazolo[3,4-
  • Step 9 6-Azetidin-3-yl-l-(l-isopropyl-azetidin-3-yl)-l,5-dihydro-pyrazolo[3,4- ⁇ /]pyrimidin-4-one dihydrochloride
  • Step 10 3-[l-(l-Isopropyl-azetidin-3-yl)-4-oxo-4,5-dihydro-lH-pyrazolo[3,4-rf]pyrimidin-6-yl]- azetidine-1-carboxylic acid (4-fluoro-phenyl)-amide
  • the reaction buffer is Tris 2OmM pH 7.4, 4 ⁇ g/mLl calmodulin, 3mM MgCl 2 , 1.5mM CaCl 2 ,
  • PDElA hydrolyses cAMP into 5'AMP; this low cAMP concentration will result in a high signal. A PDElA inhibitor will result in a decrease of the signal.
  • Phosphodiesterase Assay Kit from Biomol, a colorimetric, non-radioactive assay.
  • the basis for the assay is the cleavage of cAMP by PDElA.
  • the 5'AMP is further cleaved into the nucleoside and phosphate by the enzyme 5 '-nucleotidase (catnr KI-307).
  • the phosphate released due to enzymatic cleavage is quantified using BIOMOL GREENTM reagent (catnr AK-111) in a modified Malachite
  • the compounds of the invention are more potent against PDElA than against other PDE isoforms.
  • the compounds are 2 fold more potent against PDElA than against one or more of the other isoforms.
  • the compounds of the invention are 5 fold, particularly 10-fold, particularly 20-fold more potent against
  • the compounds of the invention are more potent against PDElA than against at least one of PDElB, PDE2A, PDE4A or PDE5A.
  • the compounds are more potent against PDElA than against at least two of PDElB, PDE2A, PDE4A or PDE5A.
  • the compounds are more potent against PDElA than against all of the other PDE isoforms.
  • lysate derived from transiently transfected HEK293 cells (transfected with PDE5A, PDElB, PDE2A or PDE4A for 48h) is used as the enzyme source.
  • the dose response of compounds on PDE5A lysate is performed using the cGMP bulk htrf kit from Cisbio (catnr 62GM2PEC).
  • the principle of this kit is based on the HTRF® technology (Homogeneous Time-Resolved Fluorescence).
  • the method is based on the competition between native cGMP and the cGMP labeled with d2.
  • the tracer binding is visualized by a monoclonal antibody against cGMP, labeled with Cryptate.
  • the specific signal i.e. energy transfer
  • PDE5A hydrolyses cGMP into 5'GMP; the decrease in cGMP concentration upon PDE5A activity will result in an increased signal.
  • a PDE5A inhibitor will cause a decrease of this signal.
  • reaction buffer consists of Tris 2OmM pH 7.4, 3mM MgCl 2 , 1.5mM CaCl 2 , 0.2mg/mL BSA and 0.001% Brij-35. After an incubation of 25 minutes at room temperature, the reaction is stopped by the addition of lO ⁇ L labeled cGMP-d2 and 10 ⁇ L anti-cGMP- Cryptate. After 1 hour incubation at room temperature, the readout is performed on the Envision (excitation 360nm; emission donor 615nm; emission acceptor 665nm).
  • the reaction buffer is Tris 2OmM pH 7.4, 37.5 U/ml calmodulin, 3mM MgCl 2 ,

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés représentés par la formule (I), qui sont des inhibiteurs de PDElA, une phosphodiestérase associée à la modulation de la dégradation du cartilage, la dégénération des articulations et les maladies associées à une telle dégradation et/ou inflammation.
PCT/EP2007/062085 2006-11-09 2007-11-08 Nouveaux composés utilisés dans le traitement de maladies dégénératives et inflammatoires WO2008055959A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US86503106P 2006-11-09 2006-11-09
US60/865,031 2006-11-09

Publications (1)

Publication Number Publication Date
WO2008055959A1 true WO2008055959A1 (fr) 2008-05-15

Family

ID=39125181

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/062085 WO2008055959A1 (fr) 2006-11-09 2007-11-08 Nouveaux composés utilisés dans le traitement de maladies dégénératives et inflammatoires

Country Status (2)

Country Link
US (1) US20090137549A1 (fr)
WO (1) WO2008055959A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009071706A1 (fr) * 2007-12-07 2009-06-11 Galapagos Nv Nouveaux composés utiles pour le traitement de maladies dégénératives et inflammatoires
WO2009071705A1 (fr) * 2007-12-07 2009-06-11 Galapagos Nv Nouveaux composés utiles pour le traitement de maladies dégénératives et inflammatoires
CN101565397B (zh) * 2009-04-07 2011-08-10 浙江医药股份有限公司新昌制药厂 N-Boc-3-氨基哌啶及其光学异构体的合成方法
US8623901B2 (en) 2009-03-31 2014-01-07 Boehringer Ingelheim International Gmbh Compounds for the treatment of CNS disorders
US8623879B2 (en) 2008-04-02 2014-01-07 Boehringer Ingelheim International Gmbh 1-heterocyclyl-1,5-dihydro-pyrazolo[3,4-D] pyrimidin-4-one derivates and their use as PDE9A modulators
US8648085B2 (en) 2007-11-30 2014-02-11 Boehringer Ingelheim International Gmbh 1, 5-dihydro-pyrazolo (3, 4-D) pyrimidin-4-one derivatives and their use as PDE9A mudulators for the treatment of CNS disorders
WO2014023191A1 (fr) * 2012-08-08 2014-02-13 中山大学 Composé pyrazolo [3, 4-d] pyrimidine cétone n-substitué et son procédé de préparation et son application
US8809345B2 (en) 2011-02-15 2014-08-19 Boehringer Ingelheim International Gmbh 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders
US8912201B2 (en) 2010-08-12 2014-12-16 Boehringer Ingelheim International Gmbh 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders
US9067945B2 (en) 2002-08-23 2015-06-30 Boehringer Ingehleim International GmbH Selective phosphodiesterase 9A inhibitors as medicaments for improving cognitive processes
US9079905B2 (en) 2008-09-08 2015-07-14 Boehringer Ingelheim International Gmbh Compounds for the treatment of CNS disorders
US9815813B2 (en) 2014-01-17 2017-11-14 Novartis Ag 1-(triazin-3-yl/pyridazin-3-yl)-piper(-azine)idine derivatives and compositions therefor for inhibiting the activity of SHP2
US10077276B2 (en) 2014-01-17 2018-09-18 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US10093646B2 (en) 2014-01-17 2018-10-09 Novartis Ag 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
EP3302484A4 (fr) * 2015-05-29 2019-01-02 Merck Sharp & Dohme Corp. Composés 6-alkyl dihydropyrazolopyrimidinone utilisés comme inhibiteurs de pde2
US10287266B2 (en) 2015-06-19 2019-05-14 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10308660B2 (en) 2015-06-19 2019-06-04 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10934285B2 (en) 2016-06-14 2021-03-02 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10975080B2 (en) 2015-06-19 2021-04-13 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10981916B2 (en) 2016-12-28 2021-04-20 Dart Neuroscience, Llc Substituted pyrazolopyrimidinone compounds as PDE2 inhibitors
JP2022511500A (ja) * 2018-12-06 2022-01-31 コリア リサーチ インスティチュート オブ ケミカル テクノロジー Ｐｄｅ９ａ阻害活性を有する化合物及びその医薬用途
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
US11434247B1 (en) 2017-11-27 2022-09-06 Dart Neuroscience Llc Substituted furanopyrimidine compounds as PDE1 inhibitors
US11919879B2 (en) 2021-06-16 2024-03-05 Celgene Corporation Carboxylic acid containing azetidinyl compounds for the treatment of neurodegenerative diseases

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2429132T3 (es) 2001-08-31 2013-11-13 The Rockefeller University Atividad de fosfodiesterasa y regulación de la señalización mediada por fosfodiesterasa 1-B en el cerebro
EP1919287A4 (fr) * 2005-08-23 2010-04-28 Intra Cellular Therapies Inc Composés organiques pour traiter un signald'activité réduit du récepteur de la dopamine
CA2651519A1 (fr) * 2006-06-06 2007-12-13 Intra-Cellular Therapies, Inc. Composes organiques
MX2010006208A (es) * 2007-12-06 2010-12-21 Intra Cellular Therapies Inc Compuestos organicos.
JP5813511B2 (ja) 2008-12-06 2015-11-17 イントラ−セルラー・セラピーズ・インコーポレイテッドＩｎｔｒａ−Ｃｅｌｌｕｌａｒ Ｔｈｅｒａｐｉｅｓ， Ｉｎｃ． 有機化合物
JP5710492B2 (ja) 2008-12-06 2015-04-30 イントラ−セルラー・セラピーズ・インコーポレイテッドＩｎｔｒａ−Ｃｅｌｌｕｌａｒ Ｔｈｅｒａｐｉｅｓ， Ｉｎｃ． 有機化合物
KR20110098732A (ko) 2008-12-06 2011-09-01 인트라-셀룰라 써래피스, 인코퍼레이티드. 유기 화합물
WO2011016861A2 (fr) 2009-08-05 2011-02-10 Intra-Cellular Therapies, Inc. Nouvelles protéines régulatrices et nouveaux inhibiteurs
WO2011153135A1 (fr) 2010-05-31 2011-12-08 Intra-Cellular Therapies, Inc. Composés organiques
EP2575817A4 (fr) 2010-05-31 2014-01-08 Intra Cellular Therapies Inc Composés organiques
US9546175B2 (en) 2014-08-07 2017-01-17 Intra-Cellular Therapies, Inc. Organic compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5294612A (en) * 1992-03-30 1994-03-15 Sterling Winthrop Inc. 6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-ones and compositions and method of use thereof
US20050148604A1 (en) * 2001-12-13 2005-07-07 Hidekazu Inoue Pyrazolopyrimidinone derivatives having PDE7 inhibiting action

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5294612A (en) * 1992-03-30 1994-03-15 Sterling Winthrop Inc. 6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-ones and compositions and method of use thereof
US20050148604A1 (en) * 2001-12-13 2005-07-07 Hidekazu Inoue Pyrazolopyrimidinone derivatives having PDE7 inhibiting action

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9067945B2 (en) 2002-08-23 2015-06-30 Boehringer Ingehleim International GmbH Selective phosphodiesterase 9A inhibitors as medicaments for improving cognitive processes
US8648085B2 (en) 2007-11-30 2014-02-11 Boehringer Ingelheim International Gmbh 1, 5-dihydro-pyrazolo (3, 4-D) pyrimidin-4-one derivatives and their use as PDE9A mudulators for the treatment of CNS disorders
WO2009071706A1 (fr) * 2007-12-07 2009-06-11 Galapagos Nv Nouveaux composés utiles pour le traitement de maladies dégénératives et inflammatoires
WO2009071705A1 (fr) * 2007-12-07 2009-06-11 Galapagos Nv Nouveaux composés utiles pour le traitement de maladies dégénératives et inflammatoires
US8623879B2 (en) 2008-04-02 2014-01-07 Boehringer Ingelheim International Gmbh 1-heterocyclyl-1,5-dihydro-pyrazolo[3,4-D] pyrimidin-4-one derivates and their use as PDE9A modulators
US9096603B2 (en) 2008-04-02 2015-08-04 Boehringer Ingelheim International Gmbh 1-heterocyclyl-1,5-dihydro-pyrazolo[3,4-D] pyrimidin-4-one derivatives and their use as PDE9A modulators
US9079905B2 (en) 2008-09-08 2015-07-14 Boehringer Ingelheim International Gmbh Compounds for the treatment of CNS disorders
US8623901B2 (en) 2009-03-31 2014-01-07 Boehringer Ingelheim International Gmbh Compounds for the treatment of CNS disorders
US9102679B2 (en) 2009-03-31 2015-08-11 Boehringer Ingelheim International Gmbh Compounds for the treatment of CNS disorders
CN101565397B (zh) * 2009-04-07 2011-08-10 浙江医药股份有限公司新昌制药厂 N-Boc-3-氨基哌啶及其光学异构体的合成方法
US9328120B2 (en) 2010-08-12 2016-05-03 Boehringer Ingelheim International Gmbh 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders
US8912201B2 (en) 2010-08-12 2014-12-16 Boehringer Ingelheim International Gmbh 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders
US8809345B2 (en) 2011-02-15 2014-08-19 Boehringer Ingelheim International Gmbh 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders
WO2014023191A1 (fr) * 2012-08-08 2014-02-13 中山大学 Composé pyrazolo [3, 4-d] pyrimidine cétone n-substitué et son procédé de préparation et son application
JP2015524447A (ja) * 2012-08-08 2015-08-24 ジョンシャン ユニバーシティＳｕｎ Ｙａｔ−Ｓｅｎ Ｕｎｉｖｅｒｓｉｔｙ Ｎ−置換ピラゾロ［３，４−ｄ］ピリミジノン類化合物、その製造方法及びその使用
US9617269B2 (en) 2012-08-08 2017-04-11 Sun Yat-Sen University N-substituted pyrazolo [3,4-D] pyrimidine ketone compound, and preparation process and use thereof
US9815813B2 (en) 2014-01-17 2017-11-14 Novartis Ag 1-(triazin-3-yl/pyridazin-3-yl)-piper(-azine)idine derivatives and compositions therefor for inhibiting the activity of SHP2
US10077276B2 (en) 2014-01-17 2018-09-18 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US10093646B2 (en) 2014-01-17 2018-10-09 Novartis Ag 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
US10968235B2 (en) 2014-01-17 2021-04-06 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US10301278B2 (en) 2014-01-17 2019-05-28 Novartis Ag 1-(triazin-3-yl/pyridazin-3-yl)-piper(-azine)idine derivatives and compositions therefor for inhibiting the activity of SHP2
US11952386B2 (en) 2014-01-17 2024-04-09 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US10336774B2 (en) 2014-01-17 2019-07-02 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US10774065B2 (en) 2014-01-17 2020-09-15 Novartis Ag 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
US11401259B2 (en) 2014-01-17 2022-08-02 Novartis Ag 1-Pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
EP3302484A4 (fr) * 2015-05-29 2019-01-02 Merck Sharp & Dohme Corp. Composés 6-alkyl dihydropyrazolopyrimidinone utilisés comme inhibiteurs de pde2
US10287266B2 (en) 2015-06-19 2019-05-14 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10308660B2 (en) 2015-06-19 2019-06-04 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10975080B2 (en) 2015-06-19 2021-04-13 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10934285B2 (en) 2016-06-14 2021-03-02 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US11905283B2 (en) 2016-06-14 2024-02-20 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10981916B2 (en) 2016-12-28 2021-04-20 Dart Neuroscience, Llc Substituted pyrazolopyrimidinone compounds as PDE2 inhibitors
US11999738B2 (en) 2016-12-28 2024-06-04 Dart Neuroscience, Llc Substituted pyrazolopyrimidinone compounds as PDE2 inhibitors
US11434247B1 (en) 2017-11-27 2022-09-06 Dart Neuroscience Llc Substituted furanopyrimidine compounds as PDE1 inhibitors
US12006325B2 (en) 2017-11-27 2024-06-11 Dart Neuroscience, Llc Substituted furanopyrimidine compounds as PDE1 inhibitors
JP2022511500A (ja) * 2018-12-06 2022-01-31 コリア リサーチ インスティチュート オブ ケミカル テクノロジー Ｐｄｅ９ａ阻害活性を有する化合物及びその医薬用途
JP7224464B2 (ja) 2018-12-06 2023-02-17 コリア リサーチ インスティチュート オブ ケミカル テクノロジー Ｐｄｅ９ａ阻害活性を有する化合物及びその医薬用途
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
US11541034B2 (en) 2020-09-03 2023-01-03 Pfizer Inc. Nitrile-containing antiviral compounds
US11452711B2 (en) 2020-09-03 2022-09-27 Pfizer Inc. Nitrile-containing antiviral compounds
US11919879B2 (en) 2021-06-16 2024-03-05 Celgene Corporation Carboxylic acid containing azetidinyl compounds for the treatment of neurodegenerative diseases

Also Published As

Publication number Publication date
US20090137549A1 (en) 2009-05-28

Similar Documents

Publication Publication Date Title
WO2008055959A1 (fr) Nouveaux composés utilisés dans le traitement de maladies dégénératives et inflammatoires
EP1689751B1 (fr) 5,7-diaminopyrazolo[4,3-d]pyrimidines a effet inhibiteur par rapport a la pde-5
AU2017258187B2 (en) Isoquinolin-3-yl carboxamides and preparation and use thereof
AU2010271270B2 (en) Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
CA2653529C (fr) Derives de pyridinone et de pyridazinone inhibiteurs de la poly(adp-ribose)polymerase (parp)
JP6105578B2 (ja) 複素環式プロテインキナーゼ阻害剤
AU2007266840B2 (en) Pyrrolo[1,2-A]pyrazin-1(2H)-one and pyrrolo[1,2-D][1,2,4]triazin-1(2H)-one derivatives as inhibitors of poly(ADP-ribose)polymerase(PARP)
US9018217B2 (en) Phenylimidazole derivatives as PDE10A enzyme inhibitors
WO2008071650A2 (fr) Nouveaux composés utiles dans le traitement de maladies dégénératives et inflammatoires
EP1463730B1 (fr) Derives de pyrazolopyridazine
CA2451525A1 (fr) Imidazotriazines utilisees comme inhibiteurs de phosphodiesterase
CA2728335A1 (fr) Nouveau derives de phenylimidazole convenant comme inhibiteurs de l'enzyme pde10a
EP2269992A1 (fr) Pyrimidinones bicycliques pour le traitement des infections
WO2008138842A1 (fr) Imidazopyrazines et triazolopyrazines pour le traitement de maladies dégénératives et inflammatoires des articulations
AU2018340475A1 (en) PDE9 inhibitor and use thereof
EP1467995B1 (fr) Composes d'antagonistes selectifs de pyrrolopyrimidine a2b ,leur synthese et leur utilisation
EP3148539B1 (fr) Inhibiteurs d'histone désacétylase, et compositions et méthodes d'utilisation de ceux-ci
EP1633756B1 (fr) Antagonistes de recepteur d'adenosine a2a
CA2791166C (fr) Composes pyrazolopyrimidines et leur utilisation comme inhibiteur de la pde10
AU2013352304A1 (en) CXCR7 antagonists
EP1874318A2 (fr) Antagonistes de nmda/nr2b a base de n-alkyl-azacycloalkyle
WO2008138843A1 (fr) Imidazopyridines et triazolopyrimidines utiles pour le traitement de maladies dégénératives et inflammatoires des articulations
EP2396333A1 (fr) Dérivés de triazolo[4,3-b]pyridazine et leurs utilisations contre le cancer de la prostate
WO2009135885A1 (fr) Composés de pyrazine fusionnée utiles dans le traitement de maladies dégénératives et inflammatoires
WO2009071707A1 (fr) Nouveaux composés utiles pour le traitement de maladies dégénératives et inflammatoires

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07822387

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07822387

Country of ref document: EP

Kind code of ref document: A1